Mevalonic acid



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- MnvALoNic ACID Cli fiord H. Shrink, Wes'tfielthand Karl Folkers, Plainiield, NJ., assignors to- Merck & Co the, Rahwa'y, N..I., a

corporation of New Jersey No Drawing. Filed Man-31,1958, Ser. No. 724,830-

' 2 Claims. (or; 260 5245 Mevalonic acid, as well as its lactone, is known to have important nutrient value and it has-been shown'thatone isomer possesses superior nutritional value over the other isomer. We have arbitrarily designated the active one as the u-isomer, and the inactive one as the fl-isomer. In the chemical manufacture of mevalonic acid both the aand the B-iso'mers, are formed simultaneously. Agensequently', it is desirable to'carr 'out a resoiuticnwhich will separate the two isomers and enable the recovery of the active a-isomer, and this is accomplished by the present invention.

The synthesis of aB-mevalonic acid may be carried out by several known processes. Representative processes are set forth in the following articles:

D. E. Wolf, C. H. Hoffman, P. E. Aldrich, H. R. Skeggs, L. D. Wright and K. Folkers, J. Amer. Chem. Soc., 78, 4499 (1956).

D. E. Wolf, C. H. Hoifman, P. E. Aldrich, H. R. Skeggs, L. D. Wright and K. Folkers, ibid., 79, 1486 (1957).

C. H. Hoffman, A. F. Wagner, A. N. Wilson, E. Walton, C. H. Shunk, D. E. Wolf, F. W. Holly and K. Folkers, ibid., 79, 2316 (1957).

In accordance with the present invention the mixture of the lactones of aand fl-mevalonic acid, which is produced by the chemical reactions of the above publications, is combined with (-|-)-a-phenyl-1-naphthalenemethylamine in the presence of a solvent for the two reactants. The solvent preferably is one which can be removed readily by vacuum distillation such as absolute ethanol or methanol or propanol.

A slight molecular excess of the amine over the lactones is desirable but not essential. The reaction should be carried out at an elevated temperature and preferably at a refluxing temperature. The reaction produces the (+)-a-phenyl-l-naphthalenemethylamide of the a-isomer and also of the B-isomer of the lactone.

This mixture of the two amides is recovered by vacuum distillation of the solvent and the mixture is then added to a solvent such as benzene from which the aand it-isomers will fractionally crystallize. The higher melting product is recovered as it contains the desired rCE u-isomer of mevalonic acid. Alkaline hydrolysis of this (+)-u-pheny1 l-naphthalene-methylamide of a-mevalonic acid yields the active a mevalonic acid. If it is desired to obtain this product in a more purified form it is combined with N,N'-dibenzylethylene diamine' and the resulting DBED salt of a-meva'lonic acid is allowed to crystallize out of a solvent.

The DBED moiety of this salt is removed by resin exchange or by neutralization with an alkali followed by' extraction of the DBED. Then, by neutralization .of the aqueous solution with an acid: it is possible to obtain the purified wmevalonic acid. The wmevalonic acid thus obtained has twice the microbiological activity of the same weight of aB-mevalonic acidwhen tested according to the procedure of HwR. Skeggs et al., I. Bact. 72, 519, (1956).

As an alternative procedure the mixture of the (+)-a phenyl-l-naphthalenemethylamides of the aand fl-mevalonic acid may be esterified by combining it with acetic anhydride in the presence of a solvent such as pyridine.

' The resulting O-acetyl derivativesare recovered by vacuum distillation of the solvent. These derivatives are added to a solvent from which the a and fi-isomers will fractional'ly crystallize. A suitable solvent is benzene to which petroleum ether has been added.

The a-isomer of the amide ester of the O-acetyl mevalonic acid is recovered, and the amide and ester components are removed by alkaline hydrolysis to yield a-meva lonicacid. This may be purified by conversion to the DBED salt as outlined above.

The following examples further illustrate the invention:

(Step A) -a-Ph'enyl-l -naphthalenemethylamia'epf ot-mevalonic acid To 8.0 g. of +)-or-pheny1-1-naphthalenemethylamine was added 4.0 g. of afi-mevalonic'acid lactone and 10 ml. of absolute ethanol. The solution was refluxed for 17 hours. Most of the ethanol was removed by evaporation under reduced pressure. The residual oil was dissolved in chloroform and extracted with three 35 ml. portions of ice-cold 1 N hydrochloric acid to remove the residual starting amine. The chloroform solution was washed with three portions of water, dried over magnesium sulfate, filtered and concentrated, leaving 9.50 g. of a viscous oil. This oil is a mixture of the amides of the u-mevalonic acid and the B-mevalonic acid.

This oil was dissolved in 60 ml. of benzene and kept at room temperature overnight. The solid that separated was the amide of the a-xnevalonic acid and it was collected, washed with benzene, and dried under'reduced pressure, wt. 6.30 g., M.P. 113-120, (a) +23 (C. 1.2 in chloroform). This crop was recrystallized from benzene six times yielding the desired product (+)-aphenyl-l-naphthalenemethylamide of ot-mevalonic acid, melting at 151 152, (a) -l-29 (C. 1.1 in form).

Analysis.Calcd. for C H NO C, 76.00, H, 6.93; N, 3.85. Found: C, 76.28; H, 6.90; N, 3.81.

(Step B) oz-Mevalom'c acid The (+)-a-phenyl-l-naphthalenemethylamide of meva- Ionic acid (0.43 -g.), melting at 15l152, was dissolved in 12 ml. of ethanol and 12 ml. of 1.0 N sodium h droxide was added. The mixture was heated in a steel bomb at 150 for three hours. The resulting solution was diluted with water, evaporated to remove the ethanol and the resulting aqueous solution was extracted with chloroform. The aqueous solution was acidified with hydrochloric acid and lyophylized. The resulting material was extracted with several portions of hot chloroform. Evaporation of the chloroform extract left salt of a-mevalonic acid The product-of Step B was dissolved in ml. of water and 0.07 .g. of N,N'-dibenzylethylenediamine in ml.

of ethanol was added. The solution was kept at room temperature overnight and then evaporated under reduced pressure to remove the ethanol. The aqueous solution was extracted with 3 x 1'-rnl.'0f' chloroform. The combined chloroform extracts were reextracted with 2 x 1 ml. of water. The aqueous extracts were combined with the first water solution. This was concentrated under reduced pressure, giving 0.10 g. of'an oil which was dissolved in 2 m1. of methanol. Ether (10 ml.) was added and the precipitate that separated was collected and washed with ether, M.P. 122-124, wt. 5 8 mg. Recrystallization from methanol-ether raised the melting point to 125126. i

AnalysisL-Calcd. for C H N O C,-62.66; H, 8.26. Found: C, 62.60; H, 8.28.

(Step Regeneration of a-inevalonic acid from the i 25 The a-mevalonic acid was obtained from the u-meva-' lonic acid DBED salt by passing an aqueous solution of the salt over an IRC-SO ion exchange resin on the. acid cycle. Removal, as by vacuum distillation, of the DBED salt water of the eluate gives qt-mevalonic acid.

EXAMPLE II (+)-a-Phenyl-1-naphthalenemethylamide of 'O-acetyl-iu mevalom'c acid The O-acetyl derivative of the amide obtained in Step A was prepared by reaction of 99 mg. of it with 0.60 ml. of acetic anhydride in 1 ml. of pyridine for hours at The solution was evaporated under reduced pressure leaving 117 mg. of a viscous oil. This was dissolved'in 4 m1. of benzene and petroleum ether (B.P. 60) was added to incipient cloudiness. The crystals that separated were collected, wt. 101 mg., M.P. 141- 147". The material was recrystallized from benzene and then from methanol, M.P. 147-148".

Analysis.--Calcd. for C H NO C, 74.05; H, 6.71; N, 3.45. Found: C, 74.33; H, 6.60; N, 3.61.

Hydrolysis of the O-acetyl derivative of the (+)-oc phenyl-l-naphthalenemethylamide of a-mevalom'c acid,

, melting at 147148 by the method described in Step B of Example I also gave a-mevalonic acid with twice the microbiological activity of the synthetic apt-compound. This a-mevalonic acid can be purified by carrying out the Steps C and D of Example I.

What is claimed is:

1. The method of recovering a-mevalonic acid from afi-mevalonic acid which includes the steps of mixing in the presence of a solvent (+)-a-phenyl-1-naphthalenemethylamine with the up-mevalonic acid lactone at elevated temperatures, removing said solvent and recovering the resulting mixture of the (+)-u-phenyl-1-naphthalenemethylamides of the uand the ,S-mevalonic acids, adding said mixture of amides to benzene to thereby obtain a selective precipitation of the amide of wmeva- Ionic acid, recovering the precipitated amide of the a-m'evalonic acid and 'hydrolyzing it to remove the amide component, and recovering the oc-mevalonic acid.

2. The process according to claim 1 in which the recovered a-mevalonic acid is further purified by mixing it with N,N'-dibenzylethylenediamine to obtain the salt,

6' allowing the salt to crystallize from a solvent, and re- 3 moving the dibenzylethylenediamine moiety to obtain purified a-mevalonic acid.

References Cited in the file of this patent UNITED STATES PATENTS 12,334,524 Wenker Nov. 16, 1943 2,539,472 Ratchford et al Jan. 30, 1951 2,829,160 Stehman et a1 Apr. 1, 1958 OTHER REFERENCES cum. Organic Chemistry, vol. 1, p. 188-9 1938 Wolf et al.: I.A.C.s. v01. 79, p.1486-7 1957 

1. THE METHOD OF RECOVERING A-MEVALONIC ACID FROM AB-MEVALONIC ACID WHICH INCLUDES THE STEPS OF MIXING IN THE PRESENCE OF A SOLVENT (+)-A-PHENYL-1-NAPHTHALENEMETHYLAMINE WITH THE AB-MEVALONIC ACID LACTONE AT ELEVATED TEMPERATURES, REMOVING SAID SOLVENT AND RECOVERING THE RESULTING MIXTURE OF THE (+)-A-PHENYL-1-NAPHTHALENEMETHYLAMIDES OF THE A-AND THE B-MEVALONIC ACIDS, ADDING SAID MIXTURE OF AMIDES TO BENZENE TO THEREBY OBTAIN A SELECTIVE PRECIPITATION OF THE AMIDE OF A-MEVALONIC ACID, RECOVERING THE PRECIPITATED AMIDE OF THE A-MEVALONIC ACID AND HYDROLYZING IT TO REMOVE THE AMIDE COMPONENT, AND RECOVERING THE A-MEVALONIC ACID. 